Project Summary Significance: Myopia (short-sightedness) results from a failure of emmetropization in which eyes grow too long for their optical power. Myopia's association with sight-threatening complications and projected near-epidemic levels world-wide (50% by 2050) make it critical that effective treatments for slowing myopia progression be developed. The chick has proved to be a very fruitful model, yielding evidence for local retinal control of eye growth and identifying multifocal (MF) lens designs that inhibit ocular elongation as potential myopia treatments. The guinea pig, a mammalian model with a fibrous sclera more like human sclera, has yielded valuable translational data. Our proposal takes advantage of our access to both models to explore optical and pharmacological avenues for myopia control under 3 aims: (1) Intravitreal (iv) atropine's anti-myopia action in chick & interactions with anti-myopia MF spectacle lenses: We will make use of our extensive experience with chicks to further investigate mechanisms underlying the anti-myopia actions of atropine and whether its combination with multifocal (MF) lenses can improve treatment efficacy. Experiments will also examine the ocular distribution of iv-injected atropine and the potential role of NO, to gain insight into whether lens- and form deprivation-induced myopia involve the same or different retinal mechanisms and sites of action of iv-injected atropine. (2) Topical atropine's anti-myopia action & interactions with MF contact lenses in guinea pigs: We will investigate in guinea pigs, the anti-myopia action of topical atropine (as used in children), with similar goals as in (1) of understanding mechanisms and whether treatment efficacy can be improved by combining MF lenses with atropine, and how atropine dosing affects treatment outcomes. Comparable data from chicks and guinea pigs will provide insight into how model choice affects mechanisms and/or outcomes. (3) Topical ocular hypotensive drugs as new avenue for myopia control in guinea pigs: We will test as potential myopia control therapies in guinea pigs, three IOP lowering drugs, latanoprost, latanoprostene (a NO- donating derivative), and brimonidine, all of which offer round-the-clock actions and can potentially offer prophylactic protection against glaucoma, for which myopes show increased susceptibility. In planned studies, we will use established RPE gene expression signatures of myopic and hyperopic growth to obtain insights into retinal contributions to growth changes; we will also apply advanced imaging and functional recording techniques, and molecular biology tools to obtain insights into treatment mechanisms and interactions (all Aims), and to characterize scleral phenotypes (Aims 2 & 3). We will also undertake pharmacological studies to investigate the ocular distribution of atropine and sensitivity changes with time (Aims 1 & 2).